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Biallelic TET2 mutations confer sensitivity to 5′-azacitidine in acute myeloid leukemia
Friedrich Stölzel, … , Martin Bornhäuser, James M. Allan
Friedrich Stölzel, … , Martin Bornhäuser, James M. Allan
Published December 8, 2022
Citation Information: JCI Insight. 2023;8(2):e150368. https://doi.org/10.1172/jci.insight.150368.
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Research Article Hematology

Biallelic TET2 mutations confer sensitivity to 5′-azacitidine in acute myeloid leukemia

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Abstract

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5′-azacitidine (5′-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5′-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5′-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.

Authors

Friedrich Stölzel, Sarah E. Fordham, Devi Nandana, Wei-Yu Lin, Helen Blair, Claire Elstob, Hayden L. Bell, Brigitte Mohr, Leo Ruhnke, Desiree Kunadt, Claudia Dill, Daniel Allsop, Rachel Piddock, Emmanouela-Niki Soura, Catherine Park, Mohd Fadly, Thahira Rahman, Abrar Alharbi, Manja Wobus, Heidi Altmann, Christoph Röllig, Lisa Wagenführ, Gail L. Jones, Tobias Menne, Graham H. Jackson, Helen J. Marr, Jude Fitzgibbon, Kenan Onel, Manja Meggendorfer, Amber Robinson, Zuzanna Bziuk, Emily Bowes, Olaf Heidenreich, Torsten Haferlach, Sara Villar, Beñat Ariceta, Rosa Ayala Diaz, Steven J. Altschuler, Lani F. Wu, Felipe Prosper, Pau Montesinos, Joaquin Martinez-Lopez, Martin Bornhäuser, James M. Allan

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Figure 2

Complete loss of TET2 expression confers a hypermethylation phenotype.

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Complete loss of TET2 expression confers a hypermethylation phenotype.
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(A) High-density array copy number profile of chromosome 4 from HEL cells showing large deletion (green bar) affecting the q arm, including TET2 (position indicated by dashed red line). (B) Immunoblot showing TET2 protein expression in 2 representative parental TET2 monoallelic HEL cell clones (HEL TET2 monoallelic) and 3 representative TET2 CRISPR/Cas9-mutated HEL cell clones (HEL TET2 biallelic). α-Tubulin was used as loading control. (C) Growth kinetics in suspension culture of HEL TET2 monoallelic (unfilled circles) and HEL TET2 biallelic (filled circles) cell clones. Cells were seeded at low density, and growth (relative to initial density) was determined at regular intervals. Data represent mean and SD of indicated number of clones from 3 independent experiments. P value calculated by 1-way ANOVA. (D) CE was calculated for HEL TET2 monoallelic (unfilled squares) and HEL TET2 biallelic (filled squares) clones after 30 days culture in soft agar. Mean and SD of indicated number of clones from 7 independent experiments are shown. P value calculated by 2-tailed Student’s t test. (E) Volcano plot demonstrating differences in CpG methylation between HEL TET2 monoallelic (n = 2) and HEL TET2 biallelic (n = 4) clones. Plot was constructed using fold-change (log2FC) values, and adjusted P values and points represent individual CpG probes, colored such that significantly differentially methylated probes (P < 0.05 and |log2FC| ≥ 2) are in red. Orange points represent probes that reach significance (P < 0.05) but are not differentially methylated (|log2FC| < 2), and black points represent nonsignificant (P ≥ 0.05) probes. (F) Unsupervised hierarchical clustering of the top 1,500 differentially methylated CpG probes across all samples resulted in distinct clustering of parental HEL TET2 monoallelic (n = 2) and HEL TET2 biallelic (n = 4) cell clones. Rows in the heatmap represent CpG probes, and vertical columns represent cell clones. Color key indicates level of methylation at CpGs.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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